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Biomedical subjects

K A Walker

Publications and source records attributed to K A Walker.

At least 19 recordsLinked to original sources
PubMed2004

Consultants in nhs scotland: a survey of work commitments, remuneration, job satisfaction and retirement plans.

BACKGROUND AND AIMS: UK consultants have reported working long hours, increased stress and reduced morale. This study set out to elicit consultants' views on flexible working and to gather data on consultants' workloads, remuneration, job satisfaction and retirement plans. As such it is the first comprehensive study of consultants in NHS Scotland. METHODS: The Information and Statistics Division of the Scottish Executive Health Dept provided a list of consultants working in NHS Scotland Focus groups and interviews informed the design of a postal self-completion, questionnaire. RESULTS: The response ratewas 61%. Almost two-thirds (65%) of respondents felt their workloads were unreasonable and unsustainable and 67% were unable to provide their desired standards of patient care. Two-thirds (67%) did not normally take meal breaks, 63% had insufficient time for outside interests, whilst 44% felt their health was being adversely affected Many (84%) believed that some of their work could be delegated to someone less qualified but 79% agreed that there were insufficient staff to make this possible. The average planned retirement age was 60 years, with 23% describing their plans as definite and 70% as quite or very likely. When asked what might induce them to postpone retirement, 50% cited reduced workload/work intensity. CONCLUSIONS: In 2003, a majority of consultants in the UK voted in favour of the new consultant contract. This will improve consultant pay and introduce a standard 40-hour working week, including worked on-call. This should address tow of the main areas of consultant dissatisfaction in NHS Scotland. However, staff shortages will require to be addressed if the contract is to be successfully implemented.

Adult↗
PubMed2003

Public opinion on systems for feeding back views to the National Health Service.

OBJECTIVES: To explore public opinions about different systems for feeding back views about health services to the National Health Service. DESIGN: Questionnaire survey. SETTING: NHS Grampian, Scotland, UK. PARTICIPANTS: A random sample of 10 000 adults registered with a general practitioner in Grampian was invited to opt in to the study; 2449 were sent questionnaires. OUTCOME MEASURES: Opinions about different feedback mechanisms and their likely effectiveness in three scenarios; reasons for preferring particular mechanisms. RESULTS: Of 1951 respondents, over 80% thought patient representatives would be a good way for people to pass on their ideas about the NHS and would help to improve it. Patient representatives were the most widely preferred course of action for two out of three scenarios. People explained their preferences for particular feedback systems mainly in terms of their ease of use, the perception that they would be listened to, and the likelihood of anything being done about what they said. However, people varied in their judgements about the likely effectiveness of different feedback systems. Preferences for particular systems varied according to the types of situation considered. Some people are reluctant to approach clinical staff with concerns about healthcare quality. A substantial minority have no confidence that their concerns would be listened to or acted upon, however they were expressed. CONCLUSION: The "patient representative" function has substantial popular support and could facilitate local learning and action to improve the quality of health services from users' perspectives. Feedback systems must demonstrate their effectiveness if they are to gain and retain public confidence.

Adult↗
PubMed2002

Changes in public awareness of, attitudes to, and use of complementary therapy in North East Scotland: surveys in 1993 and 1999.

OBJECTIVE: To assess changes in awareness of, use of, attitudes to, and opinions about complementary and alternative medicine (CAM) amongst residents of North East Scotland and to obtain details about CAM use from respondents. STUDY DESIGN: Population survey carried out in 1999, 6 years after the initial study. Postal survey to 800 people to examine eight CAMs; acupuncture, aromatherapy, chiropractic, herbalism, homeopathy, hypnotherapy, osteopathy, and reflexology. RESULTS: A total of 432/800 (54%) responded, of whom 175 (41%) had used at least one type of CAM compared to 29% in 1993. Increases in use were statistically significant for aromatherapy (18% versus 9%), acupuncture (10% versus 6%) and reflexology (9% versus 3%). A greater proportion of 1999 respondents thought CAM should be available on the NHS but a smaller proportion of respondents had concerns about using CAM (25% in 1993 and 20% in 1999). Overall concerns about effectiveness of therapies had increased from 36 to 45%, but fewer individuals were concerned about the cost of therapy in the 1999 survey (52% in 1993 to 22% in 1999). A total of 175 individuals provided details about one CAM they had used. The self-reported primary reasons for using CAM were relief of pain due to headaches or musculoskeletal problems, and for relaxation and relief of stress. The majority of CAM was therapist administered (103/166) as opposed to a bought product. Effectiveness ratings were self-reported but overall 80/166 found CAM very effective and 62/166 partially effective. A total of 65% had consulted their GP about their health problem before using CAM, 59/157 indicated their GP knew they were using CAM and of these, 14 indicated their GP was administering the therapy. CONCLUSIONS: The study has provided further baseline data on which to assess trends in CAM use and highlighted issues for patients and the NHS about the use of CAM to relieve health problems. Results indicate a greater proportion of the population of North East Scotland are both aware of and using CAM to relieve health problems. More research into the implications for the NHS of concurrent use of CAM with conventional medicine is required.

Adult↗
PubMed2001

Tubal sterilization and risk of breast cancer mortality in US women.

OBJECTIVE: To investigate the hypothesis that tubal sterilization is associated with a reduced risk of breast cancer. METHODS: We examined this hypothesis in a large prospective study of US adults. After 14 years of mortality follow-up, 3837 deaths from breast cancer were observed in a cohort of 619,199 women who were cancer-free at study entry in 1982. RESULTS: Cox proportional hazards models (adjusted for multiple breast cancer risk factors) showed a significant inverse association between tubal sterilization and breast cancer mortality (adjusted rate ratio (RR) = 0.82, 95% confidence interval (CI) 0.70-0.96). Women who were sterilized before age 35 had a lower risk (adjusted RR = 0.69, 95% CI 0.53-0.88) than women who were sterilized at 35 years of age or older (adjusted RR = 0.92, 95% CI 0.75-1.13). Also, sterilizations performed before 1975 resulted in a lower risk (RR = 0.75, 95% CI 0.62-0.91) than those performed during or after 1975 (RR = 0.98, 95% CI 0.74-1.29), possibly reflecting the likelihood of greater tissue damage with earlier procedures. CONCLUSIONS: These results suggest that tubal sterilization may lower subsequent risk of breast cancer, especially among women who are sterilized at a relatively young age. Additional studies are needed to confirm or refute these findings.

Adult↗
PubMed2000

Late-instar European corn borer (Lepidoptera: Crambidae) tunneling and survival in transgenic corn hybrids.

Field studies were conducted in 1996 and 1997 to determine injury by and survival of late-instar European corn borer, Ostrinia nubilalis (Hübner), on genetically altered Bacillus thuringiensis Berliner corn, Zea mays L. Cry1Ab events 176, Bt11, MON810, and MON802; Cry1Ac event DBT418; and Cry9C event CBH351 were evaluated. Plants of each corn hybrid were manually infested with two third-, fourth-, or fifth-instar O. nubilalis. Larvae were held in proximity to the internode of the plant above the ear with a mesh sleeve. Larvae were put on the plants during corn developmental stages V8, V16, R1, R3, R4, R5, and R6. This study shows that not all B. thuringiensis hybrids provide the same protection against O. nubilalis injury. Hybrids with B. thuringiensis events Bt11, MON810, MON802, and CHB351 effectively protected the corn against tunneling by late-instar O. nubilalis. Event 176 was effective in controlling late-instar O. nubilalis during V12 and V16 corn developmental stages; however, significant tunneling occurred by fourth instars during R3 and R5. Event DBT418 was not effective in controlling late-instar O. nubilalis during corn vegetative or reproductive stages of development. Whether the B. thuringiensis hybrids satisfied high- and ultra-high-dose requirements is discussed.

Animals↗
PubMed1999

Validation of a right hemisphere vigilance system as measured by principal component and factor analyzed quantitative electroencephalogram.

Arruda and colleagues [Arruda, J.E., Weiler, M.D., Valentino, D.A. et al., 1996. A guide for applying principal-component analysis and confirmatory factor analysis to qEEG data. Int. J. Psychophysiol. 23, 63-81.] recently described seven neurophysiological measures that were previously derived and confirmed using factor analytic procedures and the quantitative electroencephalogram (EEG) sampled from 208 normal controls during an auditory continuous performance test (CPT). The purpose of the present investigation was to further test the validity of these empirically derived measures by examining each measure's relationship with CPT-related declines in performance. Participants were 48 right-handed men (n = 13) and women (n = 35) who reported being free of any neurological condition, birthing complications, or loss of consciousness greater than 2 min. After completing an eyes-closed resting condition, participants performed a 23-min CPT while both quantitative EEG and behavioral performance were measured at 45, 405, 765 and 1125 s into the CPT. Bipolar recordings were gathered using the International 10-20 system, from eight sites: frontal, fronto-temporal, temporal and temporal-occipital. Multivariate and follow-up univariate tests suggest the existence of a neurophysiological system located within the right temporal region that appears essential for the maintenance of a sustained attentional state. If confirmed, the further quantification of this neurocognitive system may prove useful as part of a clinical diagnostic workup.

Adolescent↗
PubMed1999

Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors.

The X-ray crystal structures of the catalytic domain of human collagenase-3 (MMP-13) and collagenase-1 (MMP-1) with bound inhibitors provides a basis for understanding the selectivity profile of a novel series of matrix metalloprotease (MMP) inhibitors. Differences in the relative size and shape of the MMP S1' pockets suggest that this pocket is a critical determinant of MMP inhibitor selectivity. The collagenase-3 S1' pocket is long and open, easily accommodating large P1' groups, such as diphenylether. In contrast, the collagenase-1 S1' pocket must undergo a conformational change to accommodate comparable P1' groups. The selectivity of the diphenylether series of inhibitors for collagenase-3 is largely determined by their affinity for the preformed S1' pocket of collagenase-3, as compared to the induced fit in collagenase-1.

Amino Acid Sequence↗
PubMed1999

Functional determinants of the Escherichia coli fis promoter: roles of -35, -10, and transcription initiation regions in the response to stringent control and growth phase-dependent regulation.

Escherichia coli Fis is a small DNA binding and bending protein that has been implicated in a variety of biological processes. A minimal promoter sequence consisting of 43 bp is sufficient to generate its characteristic growth phase-dependent expression pattern and is also subject to negative regulation by stringent control. However, information about the precise identification of nucleotides contributing to basal promoter activity and its regulation has been scant. In this work, 72 independent mutations were generated in the fis promoter (fis P) region from -108 to +78 using both random and site-directed PCR mutagenesis. beta-Galactosidase activities from mutant promoters fused to the (trp-lac)W200 fusion on a plasmid were used to conclusively identify the sequences TTTCAT and TAATAT as the -35 and -10 regions, respectively, which are optimally separated by 17 bp. We found that four consecutive substitutions within the GC-rich sequence just upstream of +1 and mutations in the -35 region, but not in the -10 region, significantly reduced the response to stringent control. Analysis of the effects of mutations on growth phase-dependent regulation showed that replacing the predominant transcription initiation nucleotide +1C with a preferred nucleotide (A or G) profoundly altered expression such that high levels of fis P mRNA were detected during late logarithmic and early stationary phases. A less dramatic effect was seen with improvements in the -10 and -35 consensus sequences. These results suggest that the acute growth phase-dependent regulation pattern observed with this promoter requires an inefficient transcription initiation process that is achieved with promoter sequences deviating from the -10 and -35 consensus sequences and, more importantly, a dependence upon the availability of the least favored transcription initiation nucleotide, CTP.

Base Sequence↗
PubMed1998

The multidimensional nature of renal disease: rates and associations of albuminuria in an Australian Aboriginal community.

BACKGROUND: An epidemic of end-stage renal disease (ESRD) is accompanying the rising rates of hypertension, type 2 diabetes and cardiovascular disease among Aborigines in the Northern Territory of Australia. Incidence rates are now 21 times those of nonAboriginal Australians and are doubling every four years. We describe the rates and associations of renal disease in one remote community, which has a current ESRD incidence of 2700 per million, and cardiovascular mortality among the highest in Australia. METHODS: Between 1992 and 1995 a community-wide screening program was conducted, in which the urinary albumin/creatinine ratio (ACR) was used as the chief renal disease marker. More than 90% of the population ages five and older participated. RESULTS: Albuminuria was evident in early childhood and increased dramatically with age; 26% of adults had microalbuminuria and 24% had overt albuminuria. All renal failure developed out of a background of overt albuminuria. ACR was significantly correlated with the presence of scabies at screening, with a history of poststreptococcal glomerulonephritis, which is epidemic and endemic in the community, with increasing body wt, blood pressure, glucose, insulin and lipid levels, and with evidence of heavy drinking. ACR was also significantly and inversely correlated with birth weight. As a result of its association with deteriorating hemodynamic and metabolic profiles, increasing ACR was also correlated with increasing cardiovascular risk score. Direct observations showed, and multivariate models predicted, progressive amplification of ACR when multiple risk factors were present simultaneously. Albuminuria also clustered in families. CONCLUSION: Renal disease in this population is multifactorial, with risk factors related to whole-of-life nutrition, metabolic and hemodynamic profiles, infections, health behaviors, and possibly a family predisposition. Its relationship to low birth weight, and its associations with deteriorating metabolic and hemodynamic profiles, suggest that renal disease is, in part, a component of Syndrome X, which explains the simultaneous increase in metabolic, cardiovascular and renal disease in Aboriginal people. The family clustering might have both environmental and genetic causes, and is under further investigation. Most of the identified risk factors arise out of poverty, disadvantage and accelerated lifestyle change, and the current epidemic can be explained by the confluence of many risk factors in the last few decades. The introduction of effective and sustained programs to address social, economic and educational inequities in all Aboriginal communities, and of screening and renal- and cardiovascular-protective treatment programs for those already afflicted are matters of great urgency.

Adolescent↗
PubMed1997

A cell line selected for resistance to ionizing radiation exhibits cross resistance to other genotoxic agents and a mutator phenotype for loss of heterozygosity events.

An ionizing radiation resistant derivative was obtained from the mouse P19H22 (aprt hemizygote) embryonal carcinoma cell line by repeated exposure to 137Cs gamma radiation. Ionizing radiation resistance in the 6Gy-R cell line was not correlated with a failure to undergo cell cycle arrest or a loss of the p53 response after exposure to 137Cs gamma radiation. Moreover, the cells did not display increased resistance to bleomycin, a double strand break inducing agent. However, the cells did display increased resistance to ultraviolet radiation, ethyl methanesulfonate, and 95% oxygen. A mutational analysis demonstrated a > 700 fold-fold increase in the frequency of aprt mutants for the 6Gy-R cells, but no change in the frequency of hprt or dhfr mutants. A molecular analysis suggested that the aprt mutations in the 6Gy-R cells arose by recombinational events. A possible association between radiation resistance, DNA repair, and a mutator phenotype for large-scale mutational events is discussed.

Adenine Phosphoribosyltransferase↗
PubMed1997

Deletion analysis of the fis promoter region in Escherichia coli: antagonistic effects of integration host factor and Fis.

Fis is a small DNA-binding and -bending protein in Escherichia coli that is involved in several different biological processes, including stimulation of specialized DNA recombination events and regulation of gene expression. fis protein and mRNA levels rapidly increase during early logarithmic growth phase in response to a nutritional upshift but become virtually undetectable during late logarithmic and stationary phases. We present evidence that the growth phase-dependent fis expression pattern is not determined by changes in mRNA stability, arguing in favor of regulation at the level of transcription. DNA deletion analysis of the fis promoter (fis P) region indicated that DNA sequences from -166 to -81, -36 to -26, and +107 to +366 relative to the transcription start site are required for maximum expression. A DNA sequence resembling the integration host factor (IHF) binding site centered approximately at -114 showed DNase I cleavage protection by IHF. In ihf cells, maximum cellular levels of fis mRNA were decreased more than 3-fold and transcription from fis P on a plasmid was decreased about 3.8-fold compared to those in cells expressing wild-type IHF. In addition, a mutation in the ihf binding site resulted in a 76 and 61% reduction in transcription from fis P on a plasmid in the presence or absence of Fis, respectively. Insertions of 5 or 10 bp between this ihf site and fis P suggest that IHF functions in a position-dependent manner. We conclude that IHF plays a role in stimulating transcription from fis P by interacting with a site centered approximately at -114 relative to the start of transcription. We also showed that although the fis P region contains six Fis binding sites, Fis site II (centered at -42) played a predominant role in autoregulation, Fis sites I and III (centered at +26 and -83, respectively) seemingly played smaller roles, and no role in negative autoregulation could be attributed to Fis sites IV, V, and VI (located upstream of site III). The fis P region from -36 to +7, which is not directly regulated by either IHF or Fis, retained the characteristic fis regulation pattern in response to a nutritional upshift.

Bacterial Proteins↗
PubMed1995

Azalanstat (RS-21607), a lanosterol 14 alpha-demethylase inhibitor with cholesterol-lowering activity.

Agents that inhibit hepatic cholesterol biosynthesis reduce circulating cholesterol levels in experimental animals and humans, and may be of pharmacological importance in the prevention of atherosclerosis. Azalanstat (RS-21607), a synthetic imidazole, has been shown to inhibit cholesterol synthesis in HepG2 cells, human fibroblasts, hamster hepatocytes and hamster liver, by inhibiting the cytochrome P450 enzyme lanosterol 14 alpha-demethylase. When administered orally to hamsters fed regular chow, RS-21607 (50 mg/kg/day) lowered serum cholesterol in a dose-dependent manner (ED50 = 62 mg/kg) in a period of 1 week. It preferentially lowered low density lipoprotein (LDL) cholesterol and apo B relative to high density lipoprotein (HDL) cholesterol and apo A-1. It also lowered plasma cholesterol levels in hamsters fed a high saturated fat and cholesterol diet. RS-21607 inhibited hepatic microsomal hydroxymethylglutaryl-CoA (HMG-CoA) reductase activity in hamsters in a dose-dependent manner (ED50 = 31 mg/kg), and this was highly correlated with serum cholesterol lowering (r = 0.97). Cholesterol lowering by azalanstat and cholestyramine was additive, and the increase in HMG-CoA reductase brought about by cholestyramine was attenuated significantly by azalanstat. In vitro studies with HepG2 cells indicated that this modulation of reductase activity was indirect, occurring at a post-transcriptional step, and it is proposed that a regulatory oxysterol derived from dihydrolanosterol (or lanosterol) may be responsible for this regulation. Azalanstat does not appear to lower circulating cholesterol in the hamster by up-regulation of the hepatic LDL receptor, suggesting that other mechanisms are involved. Orally administered azalanstat (50-75 mg/kg) stimulated hepatic microsomal cholesterol 7 alpha-hydroxylase activity by 50-400% in hamsters, and it is postulated that this may result from modified cholesterol absorption and bile acid synthesis.

Acetates↗
PubMed1995

Epigenetic gene inactivation induced by a cis-acting methylation center.

In this report we test the hypothesis that a cis-acting methylation center can induce epigenetic gene inactivation. The cis-acting element used is an 838-base pair fragment that was shown previously to provide a de novo methylation signal (Mummaneni, P., Bishop, P. L., and Turker, M.S. (1993) J. Biol. Chem. 268, 552-558). Its normal location is approximately 1.3 kilobase pairs upstream of the mouse aprt (adenine phosphoribosyltransferase) gene. To determine if the methylation center could induce inactivation of the aprt gene, a plasmid construct was created in which the methylation center was moved next to the aprt promoter. Transfection experiments demonstrated inactivation of the aprt gene on the hybrid construct. The inactivation event was shown with a Southern blot analysis to correlate with hypermethylation and to be reversible by treatment with 2-deoxy-5'-azacytidine, a demethylating agent. Interestingly, gene inactivation induced by the methylation center required truncation of the aprt promoter. The results demonstrate that epigenetic gene inactivation can be induced by a DNA methylation center.

Adenine Phosphoribosyltransferase↗
PubMed1995

Spontaneous and ionizing radiation induced mutations involve large events when selecting for loss of an autosomal locus.

The mouse P19H22 embryonal carcinoma cell line contains two distinct chromosome 8 homologs, one derived from Mus musculus domesticus (M. domesticus) and the other derived from Mus musculus musculus (M. musculus). It also contains a deletion for the M. musculus aprt allele, which is located on chromosome 8. In this study, cells with spontaneous or induced aprt deficiencies were isolated from P19H22 and examined to determine the nature of the mutational events that had occurred. Ultraviolet radiation (UV), ethyl methanesulfonate (EMS), and two forms of ionizing radiation, 137Cs and 252Cf, were used for mutation induction. DNA preparations from the aprt deficient cells were initially screened with a Southern blot analysis and separated into two broad classes: those that had lost the M. domesticus aprt allele and those that had retained it. The overwhelming majority (> 95%) of the spontaneous and ionizing radiation-induced mutants exhibited aprt gene loss, indicating that relatively large events had occurred and that homozygosity for the deleted region was not a lethal event. Loss of heterozygosity for syntenic markers was found to be a common event in cells exhibiting aprt gene loss. In contrast, a majority of the UV-induced mutants (61%) and a substantial minority of the EMS-induced mutants (38%) retained the aprt gene. A sequence analysis confirmed that base-pair substitutions were responsible for this class of mutation. Gene inactivation associated with hypermethylation of the promoter region was found to be a rare event and was not induced by any of the mutagenic agents tested. The results demonstrate the suitability of the P19H22 cell line for mutational studies, particularly those that are large in nature.

Adenine Phosphoribosyltransferase↗
PubMed1994

Selective inhibition of mammalian lanosterol 14 alpha-demethylase by RS-21607 in vitro and in vivo.

The discovery of selective lanosterol 14 alpha-demethylase inhibitors may lead to novel hypolipidemic drugs. RS-21607, (2S,4S)-cis-2[1H-imidazol-1-yl)methyl]-2-[2-(4-chlorophenyl)ethyl]-4- [[(4-aminophenyl)thio]methyl]-1,3-dioxolane, was characterized as a tight-binding, competitive inhibitor of lanosterol 14 alpha-demethylase purified from rat liver. The apparent Ki was determined to be 840 pM and found to be similar in hepatic microsomes from human, rat, and hamster. RS-21607, which contains two chiral centers, was a more effective lanosterol 14 alpha-demethylase inhibitor than its three stereoisomers. In vitro, RS-21607 had a greater affinity for lanosterol 14 alpha-demethylase than the other cytochromes P450 evaluated: CYP7, CYP27, CYP11A1, CYP19, CYP17, CYP11B1, CYP21, CYP3A4, CYP4A, CYP2D6, CYP1A2, CYP2C9, and 27-hydroxycholesterol 7 alpha-hydroxylase. The other stereoisomers were not as selective as RS-21607. Doses of 3-30 mg/kg RS-21607 given orally to hamsters caused a dose-dependent decrease in cholesterol biosynthesis with a corresponding accumulation of 24,25-dihydrolanosterol. RS-21607 inhibited the enzyme and cholesterol biosynthesis in hamster liver by 50% at 18 h following a 30 mg/kg oral dose. This was interpreted to indicate that RS-21607 is able to distribute to the site of action in hamsters and inhibit the target enzyme. In the same dose range, the plasma concentrations of testosterone, corticosterone, and progesterone, the endpoints for the cytochromes P450 involved in steroid biosynthesis, were relatively unaffected. These data show RS-21607 to be an effective and selective inhibitor of lanosterol 14 alpha-demethylase, both in vivo and in vitro. RS-21607 interacted with the purified enzyme to produce a type II binding spectrum, consistent with an interaction between the imidazole moiety and the heme. The electrostatic contribution of the imidazole binding was investigated using the desimidazole analog of RS-21607. The apparent Ki for the desimidazole compound (65 microM) was similar to the apparent Km for the substrate DHL (79 microM). Together, these data confirm that the ligand attached to the imidazole in RS-21607 is a good non-sterol substitute for DHL, i.e., binding to the enzyme with similar affinity, and that the coordination of the imidazole to the heme provides a major electrostatic contribution for the inhibition of lanosterol 14 alpha-demethylase by RS-21607. RS-21607 was also observed to increase the accumulation of 3 beta-hydroxy-24,25-dihydrolanost-8-en-32-al, the second intermediate in the multistep oxidation, but not the first intermediate. 24,25-dihydrolanost-8-ene-3 beta,32-diol.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗